Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

EGG Consortium, Nicole M. Warrington, Robin N. Beaumont, Momoko Horikoshi, Felix R. Day, Øyvind Helgeland, Charles Laurin, Jonas Bacelis, Shouneng Peng, Ke Hao, Bjarke Feenstra, Andrew R. Wood, Anubha Mahajan, Jessica Tyrrell, Neil R. Robertson, N. William Rayner, Zhen Qiao, Gunn Helen Moen, Marc Vaudel, Carmen J. Marsit & 31 others Jia Chen, Michael Nodzenski, Theresia M. Schnurr, Mohammad H. Zafarmand, Jonathan P. Bradfield, Niels Grarup, Marjolein N. Kooijman, Ruifang Li-Gao, Frank Geller, Tarunveer S. Ahluwalia, Lavinia Paternoster, Rico Rueedi, Ville Huikari, Jouke Jan Hottenga, Leo Pekka Lyytikäinen, Alana Cavadino, Sarah Metrustry, Diana L. Cousminer, Ying Wu, Elisabeth Thiering, Carol A. Wang, Christian T. Have, Natalia Vilor-Tejedor, Peter K. Joshi, Jodie N. Painter, Ioanna Ntalla, Ronny Myhre, Niina Pitkänen, Elisabeth M. van Leeuwen, Raimo Joro, Elina Hypponen

Research output: Contribution to journalArticle

27 Citations (Scopus)


Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Number of pages11
JournalNature Genetics
Issue number5
Publication statusPublished - 1 May 2019

ASJC Scopus subject areas

  • Genetics

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